C5 – Complement component 5 deficiency

Complement component 5 (C5) is a central effector of the terminal complement pathway, where its cleavage into C5a and C5b initiates membrane attack complex formation and inflammatory signaling. Biallelic loss-of-function variants in C5 cause autosomal recessive complement component 5 deficiency, characterized by absent hemolytic activity and susceptibility to recurrent severe infections, notably by Neisseria species.

The first molecular lesion was an A>G transition in exon 10 (c.302A>G (p.Tyr101Cys)) that disrupts an exonic splicing enhancer, leading to exon skipping, a premature stop codon, and absence of C5 protein in a single affected patient and homozygous segregation in her pedigree ([PMID:15778377]).

Subsequent analysis of three North-African families identified homozygous deletion of three nucleotides in exon 9 (c.960_962del (p.Asn320del)) in three unrelated probands with invasive meningococcal disease; this variant was absent or at <0.1% allele frequency in 768 controls, confirming autosomal recessive inheritance ([PMID:27026170]).

A study of two additional Caucasian families uncovered three new C5 mutations, including novel nonsense and frameshift changes, and revealed one sibling with Mendelian segregation, expanding the variant spectrum to at least thirteen distinct deleterious alleles ([PMID:23743184]).

Functional assays—including CH50 hemolysis, immunodiffusion, ELISA, and Western blot—consistently demonstrated complete loss of C5 in homozygotes, while heterozygotes had half-normal levels. A murine C5-deficient model bearing a 2-base pair exon 1 deletion recapitulates the human immunodeficiency, underscoring a loss-of-function mechanism ([PMID:2303408]).

Integration of genetic and experimental data supports a Strong ClinGen classification: multiple unrelated probands (7), segregation in two families, and concordant functional studies. Clinically, C5 deficiency should be considered in patients with recurrent Neisserial infections, guiding molecular testing, carrier screening, and prophylactic strategies.

Key take-home: Biallelic C5 loss-of-function variants cause autosomal recessive complement component 5 deficiency with absent terminal pathway activity and high risk of invasive Neisseria infections.

References

• Journal of immunology • 2005 • Linking C5 deficiency to an exonic splicing enhancer mutation PMID:15778377
• Journal of clinical immunology • 2016 • Novel Mutations Causing C5 Deficiency in Three North-African Families PMID:27026170
• Immunobiology • 2013 • Primary complement C5 deficiencies - molecular characterization and clinical review of two families PMID:23743184
• The Journal of Biological Chemistry • 1990 • Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5'-exon. PMID:2303408

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